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Патент USA US2265185

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Patented Dec. 9, 1941
‘2,265,185
UNITED STATES PATENT OFFICE
2,265,185
BASIC ESTERS AND AMIDES AND PROCESS
OF PRODUCING SAME
Karl Miescher, Riehen, and Karl Hoffmann, Ba- _ ‘
sel, Switzerland, assignors, by mesne assign
ments, to Ciba Pharmaceutical Products, In
corporated, Summit, N. J., a corporation of New
Jersey
' No Drawing.
Application July 1, 1939, Serial No.
'
283,319. In Switzerland August 5, 1938
8 Claims. (Cl. 260—468)
concentrated sulfuric acid, 2 parts of activated
This invention relates to the manufacture of
platinum are added and the whole is shaken with
hydrogen at about 60° C. When reduction is ?n
ished the liquid is decanted from the platinum
basic esters and amides of alicyclic or aryl-ali
cyclic fatty acids by treating with a reducing
agent a basic ester or amide of a fatty acid con
' and the solvent is evaporated.
taining‘one or more unsaturated nuclei.
The saturation of. the unsaturated nuclear
double-linkages in accordance with the invention
may be brought about by methods in themselves
known. In this connection'reference may be
The oil which re
mains is shaken with water, potassium carbonate
solution and ether and the ethereal solution is
washed with water, dried by means of potassium
carbonate and the ether is evaporated. In this
manner thereis obtained an oil of boiling point
made to Houben-Weyl, “Die Methoden der
Organischen Chemie," 3rd edition, vol. 2, (1925),
154—157° C. under 0.2 mm. pressure. This oil is
dissolved in petroleum-ether and gaseous hydro
gen chloride is passed over the solution, whereby
the hydrochloride is precipitated: it may be re
crystallized from a, mixture of alcohol and petro
leum-ether. There is thus obtained in prepon
pages 326 et seq. Reduction by a catalytic meth
od, for instance with use of noble metals such as
platinum as catalysts, is particularly advan
tageous.
There may be used as parent materials, any
basic esters and amides of fatty acids which con
derating quantity ‘dicyclohexyl acetic acid di
tain unsaturated nuclei. There may here be
mentioned by way of example basic esters and
ethylamino ethanol ester hydrochloride of melt
ing point 165-“166° C., which is more sparingly
amides of phenyl-fatty acids, naphthalene-fatty
soluble in petroleum-ether, and a smaller quan
acids and the like. These parent materials may
be prepared according to known processes, for ex
ample‘ as described in Patents 2,079,962 and
tity of phenyl-cyclohexyl acetic acid diethyl
amino ethanol ester hydrochloride of melting
point 145—147° C., which is more readily soluble in
2,009,144.
petroleum-ether.
‘
matic carboxylic acids, for example atropine,
scopolamine, diphenyl acetic acid diethylamino
catalysts.
,
The dicyclohexyl
ethanol ester and others undergo a hydrolytic de
composition when their salts are kept in aqueous
solution. Surprisingly it has been found that the
.
.
acetic
acid-diethylamino
ethanol ester forms a sulfocyanide of melting
point 93-95° C., a nitrate of melting point
102-104° C., a tartrate of melting point 63° C. with
decomposition, a phosphate of melting point
112-114° C., a citrate of melting point 155-158° C.
new basic esters have a very considerably greater
stability. Thus for example the sulfate of di
cyclohexyl acetic acid diethylamino ethanol ester
and the hydrochloride of phenyl-cyclohexyl acetic
acid diethylamino ethanol ester can be sterilized
for 10 hours without undergoing decomposition,
whereas aqueous solutions of atropine sulfate and
of di-phenyl acetic acid diethylamino ethanol
ester hydrochloride decompose already on stand
ing for a long time at ordinary temperature and
.
There may also be used other catalysts, such as
for instance a palladium catalyst or mixture of
The hitherto known basic esters of fatty-aro 25
and an oxalate of melting point 120-124° C.
'
32 parts of dicyclohexyl acetic acid diethyl
amino ethanol'ester and 60 parts of allylbromide
are heated in 500 parts of ethyl acetate for 3
. hours to boiling, the whole is then cooled and
40
considerably more rapidly when the solution is
boiled. It is furthermore quite surprising that
?ltered. The bromallylate so obtained, having a
melting point 152-153° C., can be recrystallized
from a mixture of ethyl-acetate and acetone. In
a similar manner the following quaternary salts
of dicyclohexyl acetic acid-diethylamino ethanol
ester can also be prepared: bromomethylate.
* melting point 176-177.5°-C.: bromethylate, melt_
ing point 178-180° 0.; and bromobenzylate melt
spasmolytic activity, since all hitherto known
ing point 155-156° C.
spasmolytically active basic esters belong to the
fatty-aromatic series.
'
Example 2
The following examples illustrate the invention,
also the new esters are very active pharmacologi
cal substances. It could in no way be foreseen
, that the products of the invention would exhibit
1.5 parts of di-phenyl acetic acId-Z-diethyl
the parts being by weight:
Example 1
31 parts of di-phenyl acetic acid-2-diethyl
amino-ethyl-amide are dissolved in 20 ‘parts of
glacial acetic acid and a small quantity of con;
amino ethanol ester, are dissolved in a mixture of
200 parts of glacial acetic acid and 8 parts of
:15
centrated sulfuric acid is added. 0.1 part of
activated platinum is then added to the solution
and the whole is shaken with hydrogen at about
2
2,265,185
50° C. When the calculated quantity of hydro
tropic acid with hydrogen in the presence of
gen has been absorbed the whole is allowed to
platinum), the tau-dicyclohexyl-e-hydroxy-acetic
cool, the liquid is decanted from the platinum and
acid diethylamino ethanol ester hydrochloride
of melting point 189-191” C. (a,a-dicyclohexyl-u
hydroxy-acetic acid of melting point 143-144" C.
can be prepared for example by catalytic reduc
tion of benzilic acid), the a-phenyl-a-cyclohexyl
a-hydroxy-acetic acid diethylamino ethanol ester,
the a-cycloheXyl-hydracrylic acid scopine ester
the solvent is evaporated. To the oil which re
mains water and a sodium carbonate solution are
vadded, dicyclohexyl-acetic acid-Z-diethylamino
ethyl-amide being thereby precipitated as a solid
substance. It is ?ltered with suction and washed
with water. The new product may be recrystal
lized for example from alcohol of 50 per cent 10 hydrochloride of melting point 209-212“ C., the a
strength and has the melting point 122° C.
By conducting the reduction under somewhat
milder conditions there is obtained phenylcyclo
hexyl acetic acid diethylamino ethyl amide of
melting point 84-86“ C. which forms a hydro 15
chloride of melting point l69-l71.5° C.
'
cyclohexyl~a-propyl acetic acid diethylamino
ethanol ester hydrochloride of melting point 106
108° C. (a-cyclohexyl-a-propyl-acetic acid can be
prepared for example by a catalytic reduction of
e-phenyl-a-propyl-acetic acid with hydrogen in
glacial acetic acid solution in the presence of
platinum), the cyclohexyl-acetic acid diethyl
amino ethanol ester hydrochloride of melting
31 parts of di-phenyl acetic acid-2-diethyl
point 116-118° C., the phenyl-cyclohexyl acetic
amino-ethanol ester hydrochloride are dissolved 20 acid ester of ecgoninemethyl ester, the phenyl
in 300 parts of glacial acetic acid, 3 parts of an
dimethylaminocyclohexyl-acetic acid diethyl
activated platinum catalyst are added and the
amino ethanol ester and the cyclohexyl-diethyl
whole is shaken with hydrogen at room tempera
amino ethyl acetic acid diethylamino ethanol
Example '3
ture. The reaction mixture is worked up in the
ester.
manner indicated in Example 1, whereby there 25 What we claim is:
>
are obtained the compounds already described in
1. A process for the manufacture of basic esters
that example.
and amides, which comprises treating with a
10 parts of phenyl-cyclohexyl acetic acid di
reducing agent a member of the group consist
ethylamino ethanol ester and 6 parts of methyl
ing of the basic esters and amides of aryl sub
bromide are allowed to stand in 40 parts of ethyl 80 stituted lower fatty acids.
ester at ?rst in the cold for several hours and
2. A process for the manufacture of basic esters
then at room temperature. After some time the
and amides, which comprises treating with a re
bromomethylate of melting point 174-179" C.
ducing agent a member of the group consisting
crystallized in the form of beautiful crystals.
of the basic esters and amides of poly phenyl sub
In a similar manner there may be obtained 35 stituted lower, fatty acids.
for example the piperidino-ethanol ester, the di
3. A process for the manufacture of basic esters
ethylamino-butanol ester, the morpholino ethanol
which comprises treating with a reducing agent
‘ester, the ethyl-acetoxyethyl-amino ethanol ester,
basic esters of di-phenyl acetic acid.
. the ethyloxypropyl-amino-ethanol ester, the
4. A process for the manufacture of basic esters
methyl-propyl-amino ethanol ester and the di
which comprises treating with a reducing agent
methylaminocyclohexanol ester of the phenyl
di-phenyl acetic acid diethylamino ethanol ester.
cyclohexyl acetic acid, as well as quaternary salts
5. The nuclear reduction products of amino
of these compounds.
alkyl esters and amides of aryl substituted lower
In quite an analogous manner there can also
fatty acids.
be obtained for example the diethylamino ethanol
6. The nuclear reduction products of amino
esters of phenylcyclohexyl-propionic acid and
alkyl esters and amides of poly phenol substituted
phenylcyclohexylbutyric acid, basic esters of di
lower fatty acids.
cyclopentyl acetic acid, the dicyclohexyl acetic
7. The nuclear reduction products of amino
acid tropine ester, which forms a hydrochloride
alkyl esters of 'di-phenyl acetic acid.
of melting point 260-261" C., the u-cyclohexyl
hydracrylic acid-tropine ester sulfate of melting
point 211-213° C.‘ (a-cyclohexylhydracrylic acid
can be prepared’ for example by reduction of
8. The nuclear reduction products of di-phenyl
acetic acid diethylamino ethanol ester.
KARL MIESCHER.
KARL HOFFMANN.
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